Changes in Microvesicles as a Potential Marker of Cellular Senescence
One of the ways in which cells communicate and react to one another is via vesicles, small membrane-wrapped packets of proteins. Cell signaling in general is an important part of the detrimental effects of senescent cells on tissue function and health, and so changes in signal mechanisms might prove to be a useful marker of the presence of such cells. Now that therapies based on clearance of senescent cells are under active commercial development, there is considerable interest in the scientific community in better ways to identify and classify senescence in tissues. This open access paper is an example of the sort of research presently taking place.
Mesenchymal stem cells (MSCs) have been found to broadly distribute throughout the body and have the potential to differentiate into lineages of mesenchymal tissues such as bone, fat, and cartilage cells. Recently, MSCs have become a promising tool for cell-based therapy in tissue engineering and regenerative medicine. There is considerable evidence that MSC senescence is considered as a contributing factor to aging and aging-related diseases and replicative senescence impairs the regenerative potential of MSCs. To better understand and monitor cell senescence in MSCs, it is necessary to have a reliable biomarker for identification of these cells.
Unique phenotypic alterations of senescent MSCs have been reported including enlarged morphology, arrested proliferative capability, increased β-galactosidase activity, telomere shortening, accumulation of DNA damage, alteration of chromatin organization, reduced expression of surface antigen markers, up-regulation of cell cycle inhibitors (P16INK4A and P21WAF1), and senescence-associated secretory phenotype (SASP). Since surface and external factors can be detected without intracellular delivery of a probe and without harming the cells, they can serve as ideal biomarkers to identify senescent cells. Senescent MSCs release a specific secretome, including matrix metalloproteinases (MMP2, TIMP2), cytokines (IL-6), insulin like growth factors binding proteins (IGFBP4, IGFBP7), and monocyte chemoattractant protein-1 (MCP-1). The role of these factors has been investigated in the identification of MSC senescence.
As a key component of the cell secretome, microvesicles (MVs) are shed from cell surface by their parental cells into the extracellular environment. Recent reports indicate that these small vesicles can mirror the molecular and functional characteristics of their parental cells and participate in important biological processes, such as the surface-membrane trafficking and the horizontal transfer of proteins and RNAs among neighboring cells. A growing body of evidences has shown that MVs shed by MSCs (MSC-MVs) express MSC-related markers, which act as key effectors of MSCs. Many biological functions have been attributed to MSC-MVs, such as tissue repair, hematopoietic support, immunomodulatory regulation, and inhibition of tumor growth. Recently, it has been reported that old rat MSC-MVs have unique miRNAs and significantly inhibited TGF-β1-mediated epithelial-mesenchymal transition; however, no information is available on whether MSC-MVs could represent characteristics of their parental cells in senescence.
In the present study, we investigated the changes in MSC-MVs when their parental MSCs experienced senescence, including MSC-MV size distribution, concentration, surface antigens, osteogenesis-related functions and miRNA content, to characterize these senescent MSC-MVs and evaluate their ability to resemble their parental senescent MSCs. Our findings provide evidence that MSC-MVs are a key factor in the senescence-associated secretory phenotype of MSCs and demonstrate that their integrated characteristics can dynamically reflect the senescence state of MSCs representing a potential biomarker for monitoring MSC senescence.